JP2007513948A - Superoxide dismutase mimics for the treatment of optic nerve damage and retinal damage - Google Patents

Abstract

Disclosed are methods for preventing and treating damage to the optic nerve and / or retina using SOD mimics, particularly pentaazacycle Mn ^(II) complex SOD mimics. The present invention overcomes these and other shortcomings of the prior art by providing a method of treating a human suffering from chronic or acute optic nerve damage and / or retinal damage. This application relates to the use of specific mimetics of the enzyme superoxide dismutase to treat humans suffering from chronic or acute optic nerve damage and / or retinal damage.

Description

  This application claims priority from US patent application Ser. No. 60 / 528,830 (filed Dec. 11, 2003).

(Background of the Invention)
(1. Field of the Invention)
The present invention relates to the treatment of optic nerve damage and retinal damage resulting from ischemia and hypoxia using compounds that are mimics of the enzyme superoxide dismutase.

(2. Description of related technology)
Retinal damage or optic disc damage that can cause blindness can be caused by trauma and various pathological events including ischemia, hypoxia, or edema. There is an increasing interest in pharmacological interventions using factors that treat diseased animals such as neuroexcitotoxicity or inappropriate oxygen consumption resulting from ischemia-reperfusion injury (Clark 1999; David 1998; David). 1997).

Many disease states are facilitated, for example, by oxidative stress periods that occur during ischemia-reperfusion injury. During these periods, the body's natural defense mechanisms for processing toxic byproducts of oxidative metabolism can be overwhelmed, resulting in tissue damage from reactive oxygen species. One important component of this defense system is the superoxide dismutase (SOD) enzyme family. These enzymes are low valent metals (Mn ^II or Cu ^I / Zn ^I) that catalyze the disproportionation of highly reactive superoxide radical anions to the less toxic entities O ₂ and H ₂ O ₂ . One of the binuclear bonds). If not quenched, the superoxide anion can abstract hydrogen (through its protonated form) from the allylic site of the fatty acid, resulting in membrane damage. Furthermore, the superoxide anion can react with NO to produce peroxynitrite, as shown. This peroxynitrite is a powerful oxidant and is considered to be an important player in the harmful biological effects of excessive NO production.

Literature from the ophthalmic field shows that SOD deficiency can cause optic nerve damage, which can be rescued by administration of SOD protein. In mice injected with a ribozyme that selectively degrades SOD-2 mRNA, reduction of axons and myelin in optic disc cells and retinal ganglion cells was observed (Qi et al., 2003); , A Mn-containing superoxide dismutase and is mainly expressed in mitochondria. In SOD-2 ^{− / −} mice, attention was paid to thinning of the optic nerve fiber layer and a reduction in optic nerve cross-sectional area compared to wild-type mice (Sandbach et al., 2001). Intravitreal injection of SOD protein provided functional and histological protection in a rat ocular ischemia-reperfusion model; SOD was more effective than dimethylthiourea in terms of functional protection (99% vs. 40 %) (Rios et al., 1999).

  The superoxide oxidation of serotonin to the neurotoxin tryptamine 4,5-dione (T-4,5-D) is postulated to be a significant brain neuronal injury resulting from ischemia-reperfusion and amphetamine exposure ( Jiang and Dryhurst 2002; Wrona and Dryhurst 2001; Jiang et al., 1999; Wrona and Dryhurst 1998). T-4,5-D disrupts mitochondrial respiration through irreversible inhibition of NADH-coenzyme Q1 reductase and cytochrome c osidase, and also irreversibly inactivates tryptophan hydroxylase.

  The use of intravenously administered Mn SOD itself to treat or prevent oxidative stress related tissue injury in humans (eg, tissue damage due to cerebral ischemia reperfusion injury or myocardial ischemia reperfusion injury) Unsuccessful due to availability and immunogenicity issues. These problems are believed to be due to the fact that Mn SOD is a high molecular weight species. Low molecular weight compounds that catalyze superoxide disproportionation with efficiency comparable to endogenous Mn SOD may be good candidates for minimizing the above-mentioned side effects. Salvemini et al. Disclose a class of Mn (II) -pentazaaza macrocyclic complexes as low molecular weight SOD mimics. For example, in a rat model of intestinal ischemia reperfusion, 90% of animals dosed with 1 mg / kg of Compound 1 survived after 4 hours compared to 0% survival for untreated animals (Salvemini 1999; Patent Document 1; Salvemini et al., 2000). Compound 1 also inhibits NMDA-induced cell death in mixed neuronal / glia forebrain cell cultures (Salvemini et al., 2002a) and improves survival, reduces tissue damage, and myocardial ischemia-reperfusion injury Reduce the production of the inflammatory markers ICAM-1, P-selectin, and nitrotyrosine (Salvemini et al., 2002). These compounds are also disclosed for enhancing the stability of implanted biopolymer prosthetic devices (including ocular implants; U.S. Pat. No. 6,057,049) and for the treatment of pain (U.S. Pat. ing.

  The use of certain Mn-salen complexes as SOD mimetics and catalase mimetics with therapeutic activity is also disclosed. For example, compound 2 has been shown to be neuroprotective in a rat stroke model (Baker et al., 1998; Doctrow et al., 2002), while compound 3 lacks endogenous expression of SOD-2. Have been found to increase the lifespan of living mice (Melov et al., 2001).

Other researchers have reported the use of antioxidant compounds to treat eye diseases. Crapo et al. Disclose the use of porphyrin-containing SOD mimics to treat glaucoma and macular degeneration (US Pat. Campbell et al. Disclose the use of certain bipyridyl Mn (II or III) phenolate complexes to treat free radical-related diseases (US Pat. No. 6,057,049). Levin discloses the use of carvedilol and its derivatives and metabolites as ROS scavengers to reduce retinal ganglion cell death (US Pat. No. 6,057,049). Brownlee discloses the use of manganese tetrakis (benzoic acid) porphyrins to reduce ROS accumulation under high glucose conditions to treat diabetic retinopathy (US Pat. No. 6,057,049). A stable free radical 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl, a metal-free SOD mimetic, has been reported to inhibit light-induced retinal damage in white mice (Wang et al., 1995). However, in these reports, the compounds of the present invention are not disclosed or suggested for the treatment of optic nerve damage and retinal damage.
WO 98/58636 pamphlet International Publication No. 00/72893 A2 Pamphlet US Pat. No. 6,180,620 B1 US Pat. No. 6,214,817 B1 US Pat. No. 5,994,339 US Pat. No. 6,127,356 US Pat. No. 6,177,419 B1 International Publication No. 00/07584 A2 Pamphlet International Publication No. 00/19993 A2 Pamphlet

(Summary of the Invention)
The present invention overcomes these and other shortcomings of the prior art by providing a method of treating a human suffering from chronic or acute optic nerve damage and / or retinal damage. This application relates to the use of specific mimetics of the enzyme superoxide dismutase to treat humans suffering from chronic or acute optic nerve damage and / or retinal damage. The present invention provides compositions and methods for systemic, topical, and intraocular administration of at least one SOD mimetic in an amount effective to prevent or treat retinal damage and / or optic disc tissue damage. Disclose.

(Detailed description of the invention)
Certain SOD mimetics are currently discovered to be useful in the treatment of patients suffering from chronic or acute optic nerve damage and / or retinal damage. These compounds are of formula I:

Here, R ^1-20 is independently H, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkenyl group, an aryl group, a heteroaryl group, a heterocycloalkyl group, or a heterocycloalkenyl group. Each of these is optionally alkyl group, alkenyl group, alkynyl group, cycloalkyl group, cycloalkenyl group, aryl group, heteroaryl group, heterocycloalkyl group, heterocycloalkenyl group, halo group, trihalomethyl group, An acyl group, an alkoxycarbonyl group, an alkylsulfonyl group, or an arylsulfonyl group, or a hydroxyl group, amino group, or thiol group that is free or modified with a functional group;
Or the same site (eg, R ¹ and R ² , or R ³ and R ⁴ , or R ⁵ and R ⁶ ) or adjacent sites (eg, R ¹ and R ³ , or R ³ and R ⁵ , or R ⁶ And two of the R groups on such as R ⁷ , together with the carbon atom to which they are attached, optionally form an unsaturated or aromatic C _3-20 carbocycle, this carbon The ring is an alkyl group, alkenyl group, alkynyl group, cycloalkyl group, cycloalkenyl group, aryl group, heteroaryl group, heterocycloalkyl group, heterocycloalkenyl group, halo group, trihalomethyl group, acyl group as necessary. , An alkoxycarbonyl group, an alkylsulfonyl group, or an arylsulfonyl group, or a hydroxyl group that is free or modified with a functional group Substituted with an amino group or a thiol group;
Or the same site (eg, R ¹ and R ² , or R ³ and R ⁴ , or R ⁵ and R ⁶ ) or adjacent sites (eg, R ¹ and R ³ , or R ³ and R ⁵ , or R ⁶ and Two of the R groups on (such as R ⁷ ), together with the carbon atom to which they are attached, form an optionally unsaturated or aromatic C _2-20 nitrogen-containing heterocycle, Heterocycle is optionally alkyl group, alkenyl group, alkynyl group, cycloalkyl group, cycloalkenyl group, aryl group, heteroaryl group, heterocycloalkyl group, heterocycloalkenyl group, halo group, trihalomethyl group, acyl Group, alkoxycarbonyl group, alkylsulfonyl group, or arylsulfonyl group, or a free or functionally modified hydroxyl group Group, substituted with an amino group or a thiol group;
In all cases, when the nitrogen is already trisubstituted (eg, when the nitrogen is part of the pyridine ring), the nitrogen bound to the Mn center in the diagram for I lacks hydrogen. Is understood;
X, Y, and Z are pharmaceutically acceptable anions; and n is 0-3.

  Compounds I of the present invention are known and their synthesis is disclosed in US Pat. No. 6,214,817 B1, which is incorporated herein by reference.

  As used herein, the term “pharmaceutically acceptable anion” is suitable for therapeutic administration to a patient by any conventional means that does not have significant adverse health consequences. Means an anion. Examples of preferred pharmaceutically acceptable anions include chloride, bromide, acetate, benzoate, maleate, fumaric acid and succinate.

The term “free hydroxy group” means OH. The term “functionally modified hydroxy group” means an OH that has been functionalized to form: an alkyl group substituted with hydrogen, an ether; an acyl group substituted with hydrogen An ester; an aminocarbonyl group substituted with hydrogen; a carbamate; or an alkoxycarbonyl group substituted with hydrogen, carbonate. Examples of preferred groups include OH, OC (O) CH ₃ , OCH ₃ , OPh, OCH ₂ Ph, and OC (O) Ph.

The term “free amino group” means N ₂ . The term “functionalized amino group” means NH ₂ that has been functionalized to form: an alkoxyamino group in which one of the hydrogens is replaced by an alkoxy group or a hydroxy group. Or an hydroxyamino group; one or both of the hydrogens substituted with an alkyl group, an alkylamino group; one of the hydrogens substituted with an acyl group, an amide; an hydrogen of an alkoxycarbonyl group Carbamate, one substituted; or urea, one of the hydrogens substituted with an aminocarbonyl group. Combinations of these substitution patterns (eg, NH ₂ in which one of the hydrogens is replaced with an alkyl group and the other hydrogen is replaced with an alkoxycarbonyl group) are also amino groups modified with functional groups. And falls within the scope of the present invention. Examples of preferred _{groups, NH 2, NHCH 3, N} (CH 3) 2, NHPh, include _{NHC (O) Ph, NHC (} O) CH 3, NHC (O) OCH 3, and NHC (O) OPh It is done.

The term “free thiol group” means SH. The term “functionalized thiol group” means SH that has been functionalized to form: an alkyl group, an aryl group, a cycloalkyl group, a heterocycloalkyl group, an alkenyl group, a cycloalkenyl group. A thioether group in which hydrogen is substituted with a heterocycloalkenyl group, an alkynyl group, or a heteroaryl group; or a thioester group in which hydrogen is substituted with an acyl group. Examples of preferred _{moieties, SH, SPh, SC (O} ) CH 3, SCH 3, SC 2 H 5, SC (CH 3) 3, S- _{cyclohexyl, SCH 2 CO 2 CH 3,} SCH 2 CO 2 C 2 _{H 5, SCH 2 C (O} ) C 2 H 5, and _SCH 2 C (O) CH ₃ and the like.

  The term “acyl” refers to a group bonded by a carbon atom having a double bond to an oxygen atom and a single bond to another carbon atom.

  The term “alkyl” includes straight or branched chain aliphatic hydrocarbon groups that are saturated and have 1 to 15 carbon atoms. The alkyl group can be substituted with other groups such as halogen, hydroxyl, or alkoxy. Preferred straight chain or branched chain alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, and t-butyl.

  The term “cycloalkyl” is a linear or branched, saturated or unsaturated aliphatic hydrocarbon group linked together to form one or more rings, which may be fused or isolated. It may contain an aliphatic hydrocarbon group. The ring can be substituted with other groups such as halogen, hydroxyl, alkoxy, or lower alkyl. Preferred cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

  The term “alkenyl” includes straight or branched chain hydrocarbon groups having at least one carbon-carbon double bond and having 1 to 15 carbon atoms. The chain hydrogen can be replaced with other groups, such as halogen. Preferred straight or branched alkenyl groups include allyl, 1-butenyl, 1-methyl-2-propenyl and 4-pentenyl.

  The term “cycloalkenyl” includes a straight or branched chain saturated or unsaturated aliphatic hydrocarbon group, which is bonded to one or more non-aromatic rings containing carbon-carbon double bonds. And the ring can be fused or isolated.

  The ring can be substituted with other groups such as, for example, halogen, hydroxyl, alkoxy or lower alkyl. Preferred cycloalkenyl groups include cyclopentenyl and cyclohexenyl.

  The term “alkoxy” represents an alkyl group attached through an oxygen bond.

  The term “carbonyl group” refers to a carbon atom that is double bonded to an oxygen atom, where the carbon atom has two free valences.

  The term “alkoxycarbonyl” refers to an alkoxy group bonded from the oxygen atom of alkoxycarbonyl to the carbon of the carbonyl group, the carbonyl group itself being bonded to another atom via the carbon atom.

  The term “aminocarbonyl” refers to an amino group bonded from the nitrogen atom of aminocarbonyl to the carbon of the carbonyl group, the carbonyl group itself being bonded to another atom via the carbon atom.

The term “lower alkyl” represents an alkyl group containing ₁ to ₆ carbons (C ₁ -C ₆ ).

  The term “halogen” represents fluoro, chloro, bromo, or iodo.

  The term “aryl” refers to an aromatic, carbon-based ring. The ring can be isolated like phenyl or condensed like naphthyl. The ring hydrogen can be substituted with other groups such as lower alkyl or halogen.

  The term “heteroaryl” refers to an aromatic hydrocarbon ring containing at least one heteroatom (eg, O, S, or N) in the ring. Heteroaryl rings can be isolated with 5-6 ring atoms or can be fused with 8-10 atoms. A hydrogen or heteroatom having an open valence on the heteroaryl ring can be substituted with other groups (eg, lower alkyl or halogen). Examples of heteroaryl groups include imidazole, pyridine, indole, quinoline, furan, thiophene, pyrrole, tetrahydroquinoline, dihydrobenzofuran, and dihydrobenzindole.

Preferred compounds of the invention include compounds of formula I
Here, R ⁷ R ⁸ C—N—CR ⁹ R ¹⁰ forms a saturated or unsaturated 5- to 8-membered ring (including an aromatic ring), and this ring optionally includes an alkyl group, an alkenyl group, Alkynyl group, cycloalkyl group, cycloalkenyl group, aryl group, heteroaryl group, heterocycloalkyl group, heterocycloalkenyl group, halo group, trihalomethyl group, acyl group, alkoxycarbonyl group, alkylsulfonyl group, or arylsulfonyl group Or substituted with a free, functionally modified hydroxyl, amino or thiol group;
R ⁵ , R ⁶ , R ¹¹ , R ¹² , R ¹⁷ , R ¹⁸ , R ¹⁹ and R ²⁰ are the same or different and are H or alkyl;
R ¹ R ² C—CR ³ R ⁴ and R ¹³ R ¹⁴ C—CR ¹⁵ R ¹⁶ are the same or different and form a saturated or unsaturated 5- to 8-membered ring (including an aromatic ring). The ring is optionally substituted with an alkyl group, alkenyl group, alkynyl group, cycloalkyl group, cycloalkenyl group, aryl group, heteroaryl group, heterocycloalkyl group, heterocycloalkenyl group, halo group, trihalomethyl group, Substituted with an acyl group, an alkoxycarbonyl group, an alkylsulfonyl group, or an arylsulfonyl group, or a hydroxyl group, amino group, or thiol group that is free or functionally modified;
X and Y are chlorides; and n is 0.

  The most preferred compounds of the present invention include:

  The synthesis of these compounds is disclosed in US Pat. No. 6,214,817 B1.

  SOD mimetics can be included in various types of pharmaceutical compositions according to formulation techniques known to those skilled in the art. For example, the compounds can be tablets, capsules, solutions, suspensions, and other dosage forms adapted for oral administration; solutions and suspensions adapted for parenteral use; and local injections, ocular injections, cumulative injections, Or in solutions and suspensions adapted for intraocular injection. Solutions, suspensions, and other dosage forms applied to cumulative injections, buccal injections, intraocular injections, and local ocular administration, such as eye drops or tissue irrigation solutions, are acute or chronic, retinal damage or optic nerve Particularly preferred for the prevention or treatment of nipple damage. The composition may also be delivered locally to the eye according to the teachings in US Pat. No. 5,952,378, incorporated herein by reference.

  The compounds of formula I are believed to be effective in preventing or treating damage to the retina and optic nerve, particularly those resulting from ischemia or hypoxic stress. These compounds are also useful for treating damage resulting from the presence of a cytotoxic entity or the presence of a neurotoxic entity. These entities include, for example, glutamate and other excitatory amino acids or peptides, excess intracellular calcium, and free radicals. In particular, the compounds are useful for branch vein / arterial occlusion and central vein / arterial occlusion, pre-ischemic optic neuropathy, trauma, edema, closed angle glaucoma, open angle glaucoma, retinitis pigmentosa (RP), retinal detachment. It may be useful to treat injuries associated with laser therapy, including related injuries, photodynamic therapy (PDT) and surgical light-induced iatrogenic retinopathy. The compounds can also be used as adjuvants for ophthalmic surgery, for example by post-operative vitreous injection or subconjunctival injection. The compounds can also be used to treat acute conditions or prophylactically, especially before surgery or before non-invasive procedures.

  The invention also relates to the provision of compositions adapted for the treatment of retinal tissue and optic nerve head tissue. The ophthalmic compositions of the present invention contain one or more SOD mimetics and a pharmaceutically acceptable vehicle. Various types of vehicles can be used. This vehicle is generally water soluble in nature. Aqueous solutions are generally preferred based on ease of formulation and based on the patient's ability to easily administer such compositions by instilling 1-2 drops of solution into the affected eye. It is. However, the SOD mimetics of the present invention are also readily incorporated into other types of compositions (eg, suspensions, mucus or semi-viscous gels, or other types of solid or semi-solid compositions). Can be incorporated. Suspensions may be preferred for SOD mimetics that are relatively insoluble in water. The ophthalmic compositions of the present invention can also include various other ingredients such as buffering agents, preservatives, co-solvents, and thickeners.

  A suitable buffer system (eg, sodium phosphate, sodium acetate, or sodium borate) can be added to prevent pH fluctuations under storage conditions.

  Ophthalmic products are typically packaged in multiple dose forms. Therefore, preservatives are required to prevent microbial contamination during use. Suitable preservatives include: benzalkonium chloride, thimerosal, chlorobutanol, methyl paraben, propyl paraben, phenyl ethyl alcohol, disodium edetate, sorbic acid, polyquaternium-1, or others known to those skilled in the art Drugs. Such preservatives are typically used at a level of 0.001 to 1.0 weight / volume% (“w / v%”).

  The route of administration (eg, topical, ophthalmic, parenteral, or oral) and the dosage regimen will depend on the factors (eg, the exact nature of the condition being treated, the severity of the condition, and the age and overall of the patient Determined by a skilled clinician based on physical condition).

  In general, the dose used for the above purposes will vary, but will be effective to prevent, reduce or ameliorate retinal or optic disc tissue damage resulting from any of the above listed conditions. Out of quantity. As used herein, the term “pharmaceutically effective amount” refers to preventing chronic or acute, retinal or optic disc damage resulting from ischemia or hypoxia in a human patient, Refers to the amount of one or more SOD mimetics of the present invention that is reduced or improved. The dose used for any of the above purposes is generally about 0.01 to about 100 mg / kg body weight (mg / kg) and is administered 1 to 4 times per day. When the composition is administered topically, the composition is generally in a concentration range of 0.001 to about 5 w / v%, and 1-2 drops are administered 1 to 4 times per day. The

  The SOD mimetics of the present invention are most often used as vehicles for balanced salt irrigation solutions when administered during intraocular surgical procedures, for example via post-ocular injection or periocular injection and intraocular perfusion or infusion. preferable. BSS® sterile irrigation solution and BSS Plus® sterile intraocular irrigation solution (Alcon Laboratories, Inc., Fort Worth, Texas, USA) are examples of physiologically balanced intraocular irrigation solutions. The latter solution type is described in US Pat. No. 4,550,022, the entire contents of which are hereby incorporated by reference. Post-ocular injections or periocular injections are known to those skilled in the art and are described in many publications, for example, Ophthalmic Science: Principles of Practice (1990).

  As used herein, the term “pharmaceutically acceptable carrier” refers to a safe and suitable delivery of an effective amount of at least one compound of the invention to the desired route of administration. Refers to any formulation provided.

  The following examples are included to illustrate preferred embodiments of the invention. It should be understood by those skilled in the art that the techniques disclosed in the following examples represent techniques that are discovered by the inventor and work well in the practice of the present invention, and are therefore preferred for their implementation It can be considered to constitute a style. However, one of ordinary skill in the art appreciates that many modifications may be made in the specific embodiments disclosed in light of the present disclosure and that similar or similar results may be obtained without departing from the spirit and scope of the invention. Should be understood.

  Examples 1 and 2 below are formulations useful for intraocular, periocular, or post-ocular injection or perfusion.

  Example 1

  (Example 2)

(Example 3)
The following tablet formulations may be made according to US Pat. No. 5,049,586, incorporated herein by reference.

  The SOD mimic of the present invention is an ophthalmic irrigation solution used during ophthalmic surgery to treat retinal or optic disc damage resulting from trauma due to injury or to prevent damage resulting from the invasive nature of surgery Can be prescribed. The concentration of the SOD mimetic in the irrigation solution ranges from 0.001 to 5 w / v%.

  All of the compositions and / or methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. Although the compositions and methods of the present invention are described by preferred embodiments, variations and compositions and / or methods described herein may be used without departing from the concept, spirit and scope of the present invention. It will be apparent to those skilled in the art that it can be applied to a sequence of steps or methods. More specifically, it is clear that certain agents that are chemically and structurally related can be substituted for the agents described herein to achieve similar results. All such substitutions and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the appended claims.

(References)
The following references, to the extent that they provide exemplary, procedural, or other details that are complementary to those set forth herein, are specifically incorporated herein by reference. The

(US patent)
4,550,022, 5,049,586 5,952,378 5,994,339 6,127,356 6,177,419B1, 6,180,620B1 No. 6,214,817B1 WO98 / 58636 WO00 / 07584 WO00 / 19993A2 WO00 / 72893.

(Book)
OPHALMIC SURGERY: PRINCIPLES OF PRACTICE, (ed.), G. L. Spaeth, W.M. B. Sanders Co. , Philadelphia, Pa. U. S. A. Pp. 85-87 (1990).

(Other publications)
Baker et al., J. MoI. PHAMACOL. EXP. THER. 284: 215-221 (1998).
Clark, AF, “Current trends in antiglaucoma therapy”, EMERGING DRUGS 4: 333 (1999).
David, R, “Neuroprotection of the optical nerve in glaucoma”, ACTA OPHTHALMOL. SCAND. 75: 364 (1997).
David, R, “Changing therapeutic paradigms in glaucoma management”, EXPERT OPIN. INVEST. DRUGS 7: 1063 (1998).
Docrow et al. MED. CHEM. 45: 4549-4558 (2002).
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Jiang and Dryhurst, CHEM. RES. TOXICOL. 15: 1242-1247 (2002).
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Claims (10)

Formula I:

A method for preventing damage to the optic nerve head or retina comprising administering a pharmaceutically effective amount of a superoxide dismutase mimic of
here,
R ^1-20 is independently H, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkenyl group, an aryl group, a heteroaryl group, a heterocycloalkyl group, or a heterocycloalkenyl group, and these Each is optionally alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocycloalkyl, heterocycloalkenyl, halo, trihalomethyl, acyl Substituted with an alkoxycarbonyl group, an alkylsulfonyl group, or an arylsulfonyl group, or a hydroxyl group, amino group, or thiol group that is free or modified with a functional group;
Alternatively, the same site (eg, R ¹ and R ² , or R ³ and R ⁴ , or R ⁵ and R ⁶ etc.) or adjacent sites (eg, R ¹ and R ³ , or R ³ and R ⁵ , or R ⁶ And two of the R groups on such as R ⁷ together with the carbon atom to which they are attached, optionally form an unsaturated or aromatic C _3-20 carbocycle, The carbocycle may be an alkyl group, alkenyl group, alkynyl group, cycloalkyl group, cycloalkenyl group, aryl group, heteroaryl group, heterocycloalkyl group, heterocycloalkenyl group, halo group, trihalomethyl group, acyl as necessary. Group, alkoxycarbonyl group, alkylsulfonyl group, or arylsulfonyl group, or free or functionally modified hydroxyl Or it is substituted with an amino group or a thiol group;
Or the same site (eg, R ¹ and R ² , or R ³ and R ⁴ , or R ⁵ and R ⁶ ) or adjacent sites (eg, R ¹ and R ³ , or R ³ and R ⁵ , or R ⁶ and Two of the R groups on (such as R ⁷ ), together with the carbon atom to which they are attached, form an optionally unsaturated or aromatic C _2-20 nitrogen-containing heterocycle, Heterocycle is optionally alkyl group, alkenyl group, alkynyl group, cycloalkyl group, cycloalkenyl group, aryl group, heteroaryl group, heterocycloalkyl group, heterocycloalkenyl group, halo group, trihalomethyl group, acyl Group, alkoxycarbonyl group, alkylsulfonyl group, or arylsulfonyl group, or a free or functionally modified hydroxyl group Group, substituted with an amino group or a thiol group;
In all cases, when the nitrogen is already trisubstituted (eg, when the nitrogen is part of the pyridine ring), the nitrogen bound to the Mn center in the diagram for I lacks hydrogen. Is understood;
X, Y, and Z are pharmaceutically acceptable anions; and n is 0-3.
Method. The method of claim 1, wherein the injury is a result of ischemia and / or hypoxia. The lesions include branch vein / arterial occlusion and central vein / arterial occlusion, closed angle glaucoma, open angle glaucoma, pre-ischemic optic neuropathy, RP, retinal detachment, laser treatment, and surgical light-guided iatrogenic retina The method of claim 2, wherein the method is associated with a condition selected from the group consisting of symptoms. 2. The method of claim 1 for a compound of formula I;
R ⁷ R ⁸ C—N—CR ⁹ R ¹⁰ forms a saturated or unsaturated 5- to 8-membered ring (including an aromatic ring), and this ring is optionally an alkyl group, an alkenyl group, or an alkynyl group. Cycloalkyl group, cycloalkenyl group, aryl group, heteroaryl group, heterocycloalkyl group, heterocycloalkenyl group, halo group, trihalomethyl group, acyl group, alkoxycarbonyl group, alkylsulfonyl group, or arylsulfonyl group, or Substituted with a free, functionally modified hydroxyl, amino, or thiol group;
R ⁵ , R ⁶ , R ¹¹ , R ¹² , R ¹⁷ , R ¹⁸ , R ¹⁹ and R ²⁰ are the same or different and are H or alkyl;
R ¹ R ² C—CR ³ R ⁴ and R ¹³ R ¹⁴ C—CR ¹⁵ R ¹⁶ are the same or different and form a saturated or unsaturated 5- to 8-membered ring (including aromatic rings) The ring is optionally substituted with an alkyl group, alkenyl group, alkynyl group, cycloalkyl group, cycloalkenyl group, aryl group, heteroaryl group, heterocycloalkyl group, heterocycloalkenyl group, halo group, trihalomethyl group. Substituted with an acyl group, an alkoxycarbonyl group, an alkylsulfonyl group, or an arylsulfonyl group, or a hydroxyl group, an amino group, or a thiol group modified with a free or functional group;
X and Y are chloride; and n is 0.
Method. The compound is

The method of claim 4, wherein the method is selected from the group consisting of: Formula I:

A composition for preventing optic nerve head or retinal damage comprising administering a pharmaceutically effective amount of a superoxide dismutase mimetic of and a pharmaceutically acceptable excipient,
here,
R ^1-20 is independently H, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkenyl group, an aryl group, a heteroaryl group, a heterocycloalkyl group, or a heterocycloalkenyl group, and these Each is optionally alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocycloalkyl, heterocycloalkenyl, halo, trihalomethyl, acyl Substituted with an alkoxycarbonyl group, an alkylsulfonyl group, or an arylsulfonyl group, or a hydroxyl group, amino group, or thiol group that is free or modified with a functional group;
Alternatively, the same site (eg, R ¹ and R ² , or R ³ and R ⁴ , or R ⁵ and R ⁶ etc.) or adjacent sites (eg, R ¹ and R ³ , or R ³ and R ⁵ , or R ⁶ And two of the R groups on such as R ⁷ together with the carbon atom to which they are attached, optionally form an unsaturated or aromatic C _3-20 carbocycle, The carbocycle may be an alkyl group, alkenyl group, alkynyl group, cycloalkyl group, cycloalkenyl group, aryl group, heteroaryl group, heterocycloalkyl group, heterocycloalkenyl group, halo group, trihalomethyl group, acyl as necessary. Group, alkoxycarbonyl group, alkylsulfonyl group, or arylsulfonyl group, or a hydroxyl group that is free or functionally modified Or it is substituted with an amino group or a thiol group;
Or the same site (eg, R ¹ and R ² , or R ³ and R ⁴ , or R ⁵ and R ⁶ ) or adjacent sites (eg, R ¹ and R ³ , or R ³ and R ⁵ , or R ⁶ and Two of the R groups on (such as R ⁷ ), together with the carbon atom to which they are attached, form an optionally unsaturated or aromatic C _2-20 nitrogen-containing heterocycle, Heterocycle is optionally alkyl group, alkenyl group, alkynyl group, cycloalkyl group, cycloalkenyl group, aryl group, heteroaryl group, heterocycloalkyl group, heterocycloalkenyl group, halo group, trihalomethyl group, acyl Group, alkoxycarbonyl group, alkylsulfonyl group, or arylsulfonyl group, or a free or functionally modified hydroxyl group Group, substituted with an amino group or a thiol group;
In all cases, when the nitrogen is already trisubstituted (eg, when the nitrogen is part of the pyridine ring), the nitrogen bound to the Mn center in the diagram for I lacks hydrogen. Is understood;
X, Y, and Z are pharmaceutically acceptable anions; and n is 0-3.
Composition. 7. A composition according to claim 6, wherein for the compound of formula I:
R ⁷ R ⁸ C—N—CR ⁹ R ¹⁰ forms a saturated or unsaturated 5- to 8-membered ring (including an aromatic ring), and this ring is optionally an alkyl group, an alkenyl group, or an alkynyl group. Cycloalkyl group, cycloalkenyl group, aryl group, heteroaryl group, heterocycloalkyl group, heterocycloalkenyl group, halo group, trihalomethyl group, acyl group, alkoxycarbonyl group, alkylsulfonyl group, or arylsulfonyl group, or Substituted with a free, functionally modified hydroxyl, amino, or thiol group;
R ⁵ , R ⁶ , R ¹¹ , R ¹² , R ¹⁷ , R ¹⁸ , R ¹⁹ and R ²⁰ are the same or different and are H or alkyl;
R ¹ R ² C—CR ³ R ⁴ and R ¹³ R ¹⁴ C—CR ¹⁵ R ¹⁶ are the same or different and form a saturated or unsaturated 5- to 8-membered ring (including aromatic rings) The ring is optionally substituted with an alkyl group, alkenyl group, alkynyl group, cycloalkyl group, cycloalkenyl group, aryl group, heteroaryl group, heterocycloalkyl group, heterocycloalkenyl group, halo group, trihalomethyl group. Substituted with an acyl group, an alkoxycarbonyl group, an alkylsulfonyl group, or an arylsulfonyl group, or a hydroxyl group, an amino group, or a thiol group modified with a free or functional group;
X and Y are chloride; and n is 0.
Composition. The compound is

8. The composition of claim 7, wherein the composition is selected from the group consisting of: 7. The composition of claim 6, wherein the composition is a solution or suspension for topical ophthalmic administration, cumulative administration, or intraocular injection. 10. The composition of claim 9, wherein the concentration of the compound in the composition is 0.001 to about 5 w / v%.